Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH) (A DUE)
Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
About this trial
This is an interventional treatment trial for Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH) focused on measuring Pulmonary Arterial Hypertension, PAH, macitentan, tadalafil, fixed dose combination therapy
Eligibility Criteria
Inclusion Criteria:
- Signed and dated informed consent form (ICF)
- Confirmed diagnosis of symptomatic PAH in WHO FC II or III
Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary hypertension:
- Idiopathic
- Heritable
- Drug- or toxin-induced
- Associated with connective tissue disease, HIV infection, portal hypertension or congenital heart disease with simple systemic-to-pulmonary shunt with persistent pulmonary hypertension documented by a right heart catheterization (RHC) ≥ 1 year after surgical repair
PAH diagnosis confirmed by hemodynamic evaluation at rest (through central reading), evaluated within 5 weeks prior to randomization:
- Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, AND
- Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg, AND
- Pulmonary vascular resistance (PVR) ≥ 3 WU (i.e., ≥ 240 dyn∙sec∙cm-5)
- Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH. (Participants for whom no vasoreactivity test was performed at diagnosis can be eligible if currently treated with PAH therapy for more than 3 months and PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after introduction of their PAH therapy).
- Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the prespecified doses in the study protocol or no history of PAH-specific treatment
- Participant able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at Screening
A woman of childbearing potential must:
- have negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization
- agree to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation
- agree to follow the contraception scheme from Screening up to at least 30 days after study treatment discontinuation
Exclusion Criteria:
- Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period prior to start of treatment
- Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior to start of treatment or history of intolerance to ERA and PDE-5i combination therapy
- Hypersensitivity to any of the study treatments or any excipient of their formulations
- Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer in the 1-month period prior to start of treatment
- Treatment with a strong CYP3A4 inhibitor or a moderate dual CYP3A4/CYP2C9 inhibitor or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period prior to start of treatment
- Treatment with doxazosin
- Treatment with any form of organic nitrate, either regularly or intermittently
- Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of treatment
- Treatment with another investigational drug in the 3-month period prior to start of treatment
- Body mass index (BMI) > 40 kg/m2 at Screening
Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening:
- BMI > 30 kg/m2
- Diabetes mellitus of any type
- Essential hypertension (even if well controlled)
- Coronary artery disease, i.e. history of stable angina or known more than 50% stenosis in a coronary artery or history of myocardial infarction or history of or planned coronary artery bypass grafting and/or coronary artery stenting
- Known presence of moderate or severe obstructive lung disease any time prior to Screening as specified in study protocol
- Known presence of moderate or severe restrictive lung disease any time prior to Screening as specified in study protocol
- Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction, in the opinion of the investigator
- Known permanent atrial fibrillation, in the opinion of the investigator
- Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism)
- Documented pulmonary veno-occlusive disease
- Hemoglobin < 100 g/L (<10 g/dL) at Screening
- Known severe hepatic impairment as specified in study protocol
- Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 × upper limit of normal (ULN) at Screening
- Severe renal impairment at Screening as specified in study protocol
- Systemic hypotension at Screening or Randomization and systemic hypertension at Screening as specified in study protocol
- Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening
- Known bleeding disorder, in the opinion of the investigator
- Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic neuropathy
- Hereditary degenerative retinal disorders, including retinitis pigmentosa
- History of priapism, conditions that predispose to priapism (example, sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (example, angulation, cavernosal fibrosis, or Peyronie's disease)
- Difficulty swallowing large pills/tablets that would interfere with the ability to comply with study treatment regimen
- Any planned surgical intervention (including organ transplant) during the double-blind treatment period, except minor interventions
- Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to start of treatment, or planned to be started during the double-blind period of the study
- Pregnant, planning to become pregnant or lactating
- Any known factor or disease that might interfere with treatment adherence, full participation in the study or interpretation of the results as judged by the investigator (e.g., drug or alcohol dependence etc.)
- Known concomitant life-threatening disease with a life expectancy less than (<) 12 months
- Calcium channel blocker treatment initiated, or dose changed within 3 months prior to right heart catheterization (RHC) at screening
Sites / Locations
- St. Joseph Hearitage Healthcare
- University of Southern California
- Piedmont Healthcare
- WellStar Health System
- OSF HealthCare Cardiovascular Institute
- University of Iowa Hospitals & Clinics
- Norton Healthcare
- Sparrow Clinical Research Institute
- Minneapolis Heart Institute Foundation
- Washington University School of Medicine
- VA Sierra Nevada Health Care System
- The University of North Carolina at Chapel Hill
- Pitt County Memorial Hospital d/b/a Vidant Medical Center
- Sanford Health
- University of Cincinnati
- St. Elizabeth Hospital Mercy Bon Secors
- Legacy Hospital
- Oregon Health and Science University
- Thomas Jefferson University Hospital
- University of Pittsburgh Medical Center
- Sanford Health
- University of Texas Southwestern Medical Center
- Baylor Scott White - Plano
- WVU Health Sciences Center
- University of Wisconsin At Madison
- Medical College of Wisconsin-Froedtert Hospital
- Royal Adelaide Hospital
- Pulmonary Arterial Hypertension Clinic
- Core Research Group
- Universidade Federal De Minas Gerais - Hospital das Clínicas
- Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa
- Fundacao para o Desenvolvimento Medico Hospitalar (UNESP Botucatu)
- Secretaria da Saude do Estado do Ceara - Hospital Doutor Carlos Alberto Studart Gomes
- Universidade Federal de Goias - Hospital das Clinicas da UFG
- Hospital das Clinicas de Porto Alegre
- Irmandade Santa Casa de Misericordia de Porto Alegre
- União Brasileira de Educação e Assistência-Hospital São Lucas da PUCRS
- Hospital Das Clinicas Da Faculdade De Medicina Da USP
- SPDM - Associacao Paulista para o Desenvolvimento da Medicina - Hospital Sao Paulo
- National Heart Hospital
- University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD
- Alberta Health Services
- University of Alberta
- Vancouver General Hospital
- London Health Sciences Centre
- Beijing Anzhen Hospital
- The Second Xiangya Hospital of Central South Hospital
- The First Affiliated Hospital of Guangzhou Medical University
- Jiangsu Province Hospital
- Shanghai Pulmonary Hospital
- The General Hospital of Northern Theater Command
- Tianjin Medical University General Hospital
- The First Affiliated Hospital of Xi'an Jiaotong University
- General University Hospital II.department of Internal Medicine-cardiology and angiology
- Universitatsklinikum Bonn
- Universitätsklinikum Carl Gustav Carus Dresden
- Universitaetsklinikum Giessen
- Universitat Greifswald
- Universitaetsklinikum Hamburg Eppendorf
- Thoraxklinik am Universitätsklinikum Heidelberg
- Kardiologische Praxis Papenburg
- Universitaetsklinikum Regensburg
- Klinikum Würzburg Mitte gGmbH Standort Missioklinik
- Semmelweis Egyetem,Pulmonológiai Klinika
- Gottsegen György Országos Kardiológiai Intézet, Felnőtt kardiológiai osztály
- Pecsi Tudomanyegyetem Klinikai Kozpont
- Szegedi Tudomanyegyetem
- Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
- Cardiologia c/o Spedali Civili
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
- Azienda Ospedaliera San Gerardo
- Ospedale San Francesco
- IRCCS Policlinico San Matteo, Università degli studi di Pavi
- Policlinico Umberto I
- The University of Tokyo Hospital
- Chiba University Hospital
- Kyushu University Hospital
- Fukushima Medical University Hospital
- Gunma University Hospital
- Kure Kyosai Hospital
- Tokai University Hospital
- Kagoshima University Hospital
- Kanazawa University Hospital
- Kobe University Hospital
- Kumamoto University Hospital
- Kurume University Hospital
- University Hospital Kyoto Perfectural University of Medicine
- Kyoto University Hospital
- Shinshu University Hospital
- Kyorin University Hospital
- Nagasaki University Hospital
- Okayama University Hospital
- National Hospital Organization Okayama Medical Center
- Hokkaido University Hospital
- Sapporo Medical University Hospital
- Tohoku University Hospital
- National Cerebral and Cardiovascular Center
- Juntendo University Hospital
- University of Tsukuba Hospital
- Mie University Hospital
- Institut Jantung Negara (National Heart Institute)
- Sarawak Heart Center
- Instituto Nacional de Cardiologia Dr. Ignacio Chavez
- Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)
- Klinika Kardiologii z Oddzialem Intensywnego Nadzoru Kardiologicznego, UM w Białymstoku
- Szpital Uniwersytecki nr 2 im dr Jana Biziela w Bydgoszczy, Klinika Kardiologii
- Uniwersyteckie Centrum Kliniczne
- GCM SUM, I Oddzial Kardiologii
- Oddzial Kardiologii Wojewodzki Szpital Specjalistyczny im. W.Bieganskiego
- Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego SPZOZ, Oddzial Kardiologii
- ECZ Otwock Klinika Kardiologii, Klinika Krążenia Płucnego Chorób Zakrzepowo-Zatorowych i Kardiologii
- SPSK2 PUM, Klinika Kardiologii
- Wojewodzki Szpital Specjalistyczny, Oddzial Kardiologiczny
- Altay Regional Cardiological Dispensary
- Scientific and Research Institution of Cardiovascular Diseases Complex Problems
- National Medical Research Center of Cardiology of MoH of Russian Federation
- GU Moscow Regional Research Clinical Institute n.a. M.F.Vla
- National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation
- Samara Regional Clinical Cardiological Dispensary
- Abdullah, IA
- Dr Kalla
- Hosp. Clinic I Provincial de Barcelona
- Hosp. Univ. Vall D Hebron
- Hosp. Univ. Ramon Y Cajal
- Hosp. Univ. Fund. Jimenez Diaz
- Hosp. Univ. La Paz
- Hosp. Clinico Univ. de Salamanca
- Hosp. Univ. Marques de Valdecilla
- Hosp. Virgen de La Salud
- Hosp. Gral. Univ. Valencia
- Kaohsiung Veterans General Hospital
- National Cheng Kung University Hospital
- National Taiwan University Hospital
- Mackay Memorial Hospital
- Taipei Veterans General Hospital
- Chang-Gung Memorial Hospital, LinKou Branch
- Cukurova University Medical Faculty
- Hacettepe University Medical Faculty
- Ankara University Medical Faculty
- Bursa Yuksek Ihtisas Training and Research Hospital
- Istanbul University - Cerrahpasa Cardiology Institution
- Istanbul University Cerrahpasa Medical Faculty
- Marmara University Medical Faculty
- Ege University School of Medicine
- Dokuz Eylul University Hospital
- Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi
- Konya Selcuk University Medical Faculty
- Mersin University Medical Faculty
Arms of the Study
Arm 1
Arm 2
Arm 3
Experimental
Active Comparator
Active Comparator
FDC therapy + Placebo macitentan + Placebo tadalafil
Macitentan mono-therapy + Placebo tadalafil + Placebo FDC
Tadalafil mono-therapy + Placebo macitentan + Placebo FDC
Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments.
Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments.
Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.